---according to this Cochrane review. Med Page Today commentary here. The Cochrane reviewers were only able to find two studies that met their criteria: Randomised trials of augmentation therapy with alpha-1 antitrypsin compared with placebo or no treatment. Both looked at surrogate endpoints and neither addressed mortality. One surrogate endpoint (change in CT lung density) showed a statistically significant difference favoring treatment but the clinical significance is not known. There was no difference in exacerbations, quality of life of other endpoints.
I am not familiar with the primary literature on treatment of alpha-1 so this report raises more questions than answers for me. The medical press has hyped this somewhat but it's not as if it should be breaking news given that there were only two high level trials, both essentially negative, such that it wouldn't have taken a statistician to figure it out.
Professional societies endorse replacement therapies in their guidelines. Surely they were already aware of this literature. I have no idea whether this will change their recommendations for treatment. The important point is not that the treatment doesn't work (it seems to improve at least one surrogate endpoint and may ease the severity, although not the frequency, of exacerbations) but that we need a large RCT looking at mortality and other hard clinical endpoints, something like the National Emphysema Treatment Trial.
What about screening? Screening is widely advocated and has been widely believed to be underperformed. Although it will be interesting to see what the next round of guidelines say I will not change my approach that all patients with COPD or unremitting asthma should be screened. Screening is easy to do, is important for non-pulmonary disease associations and may still have treatment implications.
2 comments:
Thank you for a remarkably thoughtful response to the Gøtzsche review, Dr. Donnell.
The Alpha-1 Foundation has challenged the Gøtzsche review as “so flawed in its methodology that it may threaten the reputation of the Cochrane Library.”
Foundation President & CEO John Walsh said, “We hope that therapies for other rare conditions won’t become victims of the same poorly designed analysis.”
Doctors with an international reputation for research on Alpha-1 Antitrypsin Deficiency are criticizing the Gøtzsche review. Among them is the scientist who was lead author of the only two studies cited by Gøtzsche.
Danish researcher Asger Dirksen, MD, who was originally listed as a co-author of the Gøtzsche review, had his name removed before publication. Said Dirksen, the lead author of the two studies cited by Gøtzsche: “After seeing the first draft I realized that our points of view were so far apart that collaboration with Peter Gøtzsche and his wife (Helle Krogh Johansen) would not be possible.”
Robert Stockley, MD, Director of Research and Development at Queen Elizabeth Hospital, Birmingham, UK, had this critique:
“This conclusion was based on retrospective analysis of published data from only two small pilot placebo-controlled studies that were not powered to evaluate the effectiveness of augmentation therapy. This flies in the face of carefully crafted guidelines from the American Thoracic Society, the European Respiratory Society, the American College of Chest Physicians, and the American Association for Respiratory Care – all prestigious organizations that recommend augmentation therapy for the treatment of patients with lung disease due to Alpha-1. The guidelines are based on the totality of the evidence, scientific understanding of the disease, correcting the biochemical defect, and a wealth of observational studies.”
Augmentation therapy is the only available specific treatment for the lung disease associated with Alpha-1, a rare genetic condition. The therapy supplements the missing protein, alpha-1 antitrypsin, in the blood of individuals with Alpha-1, using alpha-1 antitrypsin protein purified from the plasma of healthy donors. Originally developed by National Institutes of Health researchers in the early 1980s, augmentation therapy has been approved by the US Food and Drug Administration (FDA) for more than 20 years.
The Alpha-1 Foundation points out that the Gøtzsche publication relies on combining the results of these two small randomized, placebo-controlled trials (each enrolling less than 100 study subjects), and is not based on the raw data from these studies. The review neglects the fact that the two studies had a significant number of individuals who enrolled in both studies and hence should not be included twice in combined analysis as this biases the data.
“The article also discards an important endpoint of both studies, the evaluation of loss of lung tissue as judged by CT scans, as being of no clinical interest. In fact, CT scans are the most direct method for evaluating the extent and progression of emphysema – the primary lung disease suffered by those with Alpha-1 – and now accepted as the best predictor of mortality in this disease,” said Robert A. Sandhaus, MD, PhD, Alpha-1 Foundation Clinical Director. “The meta-analysis by Gøtzsche did show a benefit of augmentation therapy in reducing the loss of lung tissue as measured by chest CT.”
Sandhaus said the review also “overlooks the effect of study dropouts related to worsening lung function in the placebo groups, which unbalances the differences in treatment groups."
The Foundation’s Medical and Scientific Advisory Committee, along with several recognized experts in the international scientific community, both in the USA and Europe, is currently preparing a formal response to the Gøtzsche article.
The Foundation’s complete press release on the Gøtzsche article can be found on its website, www.alpha-1foundation.org.
Thanks for your thoughtful response to this review, Dr. Donnell.
The Alpha-1 Foundation has challenged the Gøtzsche review as “so flawed in its methodology that it may threaten the reputation of the Cochrane Library.”
Foundation President & CEO John Walsh said, “We hope that therapies for other rare conditions won’t become victims of the same poorly designed analysis.”
Doctors with an international reputation for research on Alpha-1 Antitrypsin Deficiency are criticizing the Gøtzsche review. Among them is the scientist who was lead author of the only two studies cited by Gøtzsche.
Danish researcher Asger Dirksen, MD, who was originally listed as a co-author of the Gøtzsche review, had his name removed before publication. Said Dirksen, the lead author of the two studies cited by Gøtzsche: “After seeing the first draft I realized that our points of view were so far apart that collaboration with Peter Gøtzsche and his wife (Helle Krogh Johansen) would not be possible.”
The Foundation’s complete press release on the Gøtzsche article can be found on its website, www.alpha-1foundation.org.
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